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Targeting the PHB2-ACSL3 Lipid-Remodeling Axis Overcomes Cisplatin Resistance by Restoring Ferroptosis in Gastric
Liang Xu1,2,3, Wanying Xiang1,4, Xinyue Wang1
1Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
Abstract:
Platinum-based chemotherapy resistance remains a major obstacle in gastric cancer (GC) treatment. Through integrated transcriptomic profiling of cisplatin-resistant xenografts and pharmacogenomic interrogation of the NCI-60 dataset, we identified Prohibitin-2 (PHB2) as a previously unrecognized determinant of chemoresistance. PHB2 was consistently upregulated in resistant tumors and associated with poor clinical outcomes. Mechanistically, PHB2 binds the lipid-metabolic enzyme ACSL3 through a defined AMP-binding-domain interface (residues W244/H254/E260), enhancing ACSL3 activity to promote monounsaturated fatty acid incorporation into phospholipids. This phospholipid remodeling suppresses lipid peroxidation and establishes a ferroptosis-resistant state. Structure-based virtual screening of an FDA-approved drug library nominated the CXCR4 antagonist Mavorixafor as a potent inhibitor of the PHB2-ACSL3 interaction. Mavorixafor disrupted lipid remodeling, restored ferroptosis susceptibility, and resensitized cisplatin-resistant GC in cell line-derived xenografts (CDOs) and patient-derived organoids (PDOs). The therapeutic effect was abrogated by the ferroptosis inhibitor Liproxstatin-1, confirming ferroptosis dependence. Collectively, our findings define a PHB2-ACSL3 lipid-metabolic axis that drives ferroptosis escape and identify Mavorixafor repurposing as an immediately translatable strategy to overcome cisplatin resistance in treatment-refractory GC.
Insights
Chemoresistance in gastric cancer is linked to Prohibitin-2 (PHB2), which blocks ferroptosis. The drug Mavorixafor targets this pathway, restoring chemo-sensitivity and offering a new treatment strategy for refractory gastric cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Platinum-based chemotherapy resistance is a significant challenge in gastric cancer (GC) treatment.
- Identifying novel targets is crucial for overcoming chemoresistance and improving patient outcomes.
Purpose of the Study:
- To identify novel determinants of chemoresistance in gastric cancer.
- To investigate the role of Prohibitin-2 (PHB2) in cisplatin resistance.
- To explore Mavorixafor as a potential therapeutic agent to resensitize gastric cancer to chemotherapy.
Main Methods:
- Integrated transcriptomic profiling of cisplatin-resistant xenografts.
- Pharmacogenomic interrogation of the NCI-60 dataset.
- Biochemical assays to elucidate the PHB2-ACSL3 interaction and its functional consequences.
- In vitro and in vivo studies using cell line-derived xenografts (CDXs) and patient-derived organoids (PDOs).
Main Results:
- Prohibitin-2 (PHB2) was identified as a key determinant of chemoresistance, upregulated in resistant tumors and associated with poor prognosis.
- PHB2 enhances ACSL3 activity, promoting phospholipid remodeling that suppresses lipid peroxidation and induces ferroptosis resistance.
- Mavorixafor, a CXCR4 antagonist, inhibited the PHB2-ACSL3 interaction, disrupted lipid remodeling, restored ferroptosis susceptibility, and resensitized cisplatin-resistant GC.
- Therapeutic efficacy of Mavorixafor was confirmed to be ferroptosis-dependent.
Conclusions:
- A PHB2-ACSL3 lipid-metabolic axis drives ferroptosis escape in gastric cancer, contributing to cisplatin resistance.
- Mavorixafor repurposing represents a promising and immediately translatable strategy to overcome cisplatin resistance in refractory gastric cancer.
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